- The known systemic effects of pituitary-derived melanocortin peptides result primarily from ACTH-mediated adrenocortical glucocorticoid production. The identification of a widely-distributed peripheral receptor for ACTH/MSH peptides, called the melanocortin-5 receptor (MC5-R), raises the possibility of non-steroidally mediated systemic effects of these peptides. Targeted disruption of the MC5-R produced a mouse with a severe defect in water repulsion and thermoregulation due to a defect in the production of sebaceous lipids. Further investigation demonstrated high levels of MC5-R in multiple exocrine tissues, including the Harderian, preputial, lacrimal, and sebaceous glands. The MC5-R is also required for the production of porphyrins by the Harderian gland, and regulation of protein secretion by the lacrimal gland via the MC5-R. The data show a requirement for the MC5-R in multiple exocrine glands for the production of a diverse set of products, including lipids, proteins, and porphyrins, and suggest the existence of a coordinated system for the regulation of exocrine gland function by melanocortin peptides. The MC5-R may thus have clinical applications to a number of human diseases involving exocrine gland dysfunction, such as acne, dry eye syndromes, and blepharitis. In this application the investigator proposes to characterize the extent of expression of the MC5-R in exocrine tissues, to begin to identify exocrine gland products whose production and secretion is regulated by the MC5-R, to examine the physiological significance of this regulation, and to determine the potential utility of MC5-R agonists and antagonists for the regulation of exocrine gland function in vivo, using the mouse as a model.